Project Summary Intra-Uterine Growth Restriction (IUGR) complicates 5-10% of all pregnancies in the U.S.A and currently has no treatment. The majority of these cases are due to placental insufficiency and studies indicate that these babies are at high risk of developing obesity, diabetes and cardiovascular disease in adulthood. The long-term goal is to establish an independent laboratory with research interests in placental function and programming following placental gene transfer in order to establish potential treatment strategies for fetal growth restriction. The overall objective of this application is to develop vectors for placental Insulin-like Growth Factor 1 gene transfer in a mouse model of growth restriction and gain new insight into the placental mechanisms of IGF-1. My central hypothesis is that increased placental nutrient transport induced by over-expression of IGF-1 following IGF-1 gene therapy constitutes one mechanism responsible for the correction of fetal growth restriction by gene therapy. The hypothesis has been formulated on the basis of preliminary data produced in the applicants and mentors laboratory. The rationale behind this proposal is that it is expected to broaden the knowledge of IGF-1 actions in the placenta in vivo and yield new technologies for placental gene transfer while, at the same time, it provides the means of establishing the Candidate as an independent researcher. To test the central hypothesis and accomplish the objective of this application the candidate intends to pursue the following specific aims: 1) To demonstrate that intraplacental gene transfer of IGF-1 corrects placental insufficiency and restores placental, fetal and postnatal growth in a mouse model of IUGR (to be accomplished during the mentored phase) and 2) To determine if the correction of fetal growth restriction following IGF-1 gene transfer is due to increased placental nutrient transport (to be accomplished during the independent phase). Under the first aim the candidate will receive training in gene therapy techniques and develop strategies for placental IGF-1 gene transfer, after which the effect of over-expression of IGF-1 in the placenta on placental growth and development and fetal and post-natal growth will be analyzed. Under the second aim functional and molecular studies in vitro and in vivo will identify the involvement of placental nutrient transport in IGF-1 mediated fetal growth recovery and provide insight into placental IGF-1 mechanisms. The use of site- specific intraplacental gene transfer of IGF-1 is highly innovative, challenging current paradigms for the management of IUGR and may provide new insights into the placental mechanisms of IGF-1. It also provides an experimental means to test Barker's fetal programming hypothesis and to prevent adult diseases such as obesity, diabetes, hypertension and cardiovascular disease. The proposed research is significant because it has the potential to move the field forward in the development of and understanding of the mechanisms of placental gene therapy strategies and furthering our knowledge of IGF-1 function in the placenta. Ultimately such knowledge has the potential to lead to the development of the first effective treatment for IUGR.